The prevalence of nicotine dependence, its accompanying health problems, and the difficulty users have in maintaining abstinence combine to make it one of the most problematic abused drugs in our society. These studies were designed to provide a better understanding of the pathophysiology and mechanisms of nicotine dependence as well as to contribute to the development of putative new smoking cessation treatments. Several nicotine delivery systems have been developed to aid in smoking cessation. Two of these, nicotine polacrilex and nicotine transdermal patches, have been approved for this purpose. However, new systems are being developed, including a nicotine nasal spray and a nicotine vapor inhaler. These systems are notable for having a more rapid delivery rate, a factor that has been associated with greater potential for abuse. Therefore, although developed as aids for smoking cessation, such systems may be abused in their own right. The first study was designed to examine the physiological, subjective and performance effects of various doses of nicotine nasal spray and vapor inhaler compared to a regular cigarette, which served as a standard positive control. This placebo-controlled, double blind, outpatient study will provide needed information about the abuse liability of these products. Although it is commonly thought that cotinine, the major metabolite of nicotine, has insignificant pharmacologic activity, cotinine has been shown to be behaviorally active in both humans and other animals. Of particular interest is the recent finding that cotinine administration induces subjective changes in abstinent human cigarette smokers. The purpose of the second study is to characterize the pharmacodynamic effects of cotinine in cigarette smokers undergoing periodic abstinence, including symptoms of tobacco withdrawal, mood and subjective state, drug effect, performance, and endocrine effects. This study, which is in progress, will provide valuable information on a neglected aspect of the pharmacology of tobacco dependence. In addition, if cotinine is effective in suppressing withdrawal, a new pharmacologic treatment may be developed, which could save hundreds of thousands of lives each year in the United States.